RIP3 AND pMLKL promote necroptosis-induced inflammation and alter membrane permeability in intestinal epithelial cells

Anna Negroni, Eleonora Colantoni, Maria Pierdomenico, Francesca Palone, Manuela Costanzo, Salvatore Oliva, Antonio Tiberti, Salvatore Cucchiara, Laura Stronati

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Abstract

Background Necroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). Aims The aim of this study is to examine in depth in vitro and ex vivo the contribution of necroptosis to intestinal inflammation. Methods In vitro: we used an intestinal cell line, HCT116RIP3, produced in our laboratory and overexpressing RIP3. Ex vivo: intestinal mucosal biopsies were taken from patients with inflammatory bowel disease (IBD) (20 with Crohn's disease; 20 with ulcerative colitis) and from 20 controls. Results RIP3-induced necroptosis triggers MLKL activation, increases cytokine/alarmin expression (IL-8, IL-1β, IL-33, HMGB1), NF-kBp65 translocation and NALP3 inflammasome assembly. It also affects membrane permeability by altering cell–cell junctional proteins (E-cadherin, Occludin, Zonulin-1). Targeting necroptosis through Necrostatin-1 significantly reduces intestinal inflammation in vitro and in cultured intestinal explants from IBD. Conclusion We show for the first time in vitro and ex vivo that RIP3-driven necroptosis seriously affects intestinal inflammation by increasing pMLKL, activating different cytokines and alarmins, and altering epithelial permeability. The inhibition of necroptosis causes a significant decrease of all these effects. These data strongly support the view that targeting necroptosis may represent a promising new option for the treatment of inflammatory enteropathies.
Original languageEnglish
Pages (from-to)1201 - 1210
Number of pages10
JournalDigestive and Liver Disease
Volume49
Issue number11
DOIs
Publication statusPublished - 1 Nov 2017
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Negroni, A., Colantoni, E., Pierdomenico, M., Palone, F., Costanzo, M., Oliva, S., Tiberti, A., Cucchiara, S., & Stronati, L. (2017). RIP3 AND pMLKL promote necroptosis-induced inflammation and alter membrane permeability in intestinal epithelial cells. Digestive and Liver Disease, 49(11), 1201 - 1210. https://doi.org/10.1016/j.dld.2017.08.017